This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT Children undergoing stem cell transplantation (SCT) often require prolonged courses of parenteral nutrition (PN) to maintain nutritional status during the engraftment period. Although PN has been associated with shorter engraftment time and decreased mortality in these patients, it may also be associated with significant complications, including infections, liver disease, and metabolic disturbances. Some of these complications may be related to providing excessive amounts of parenteral nutrition (overfeeding), although underfeeding is also associated with adverse nutritional and metabolic outcomes. Nutrient and energy needs of children undergoing SCT are not well known, and current practice calls for providing 130-150% of estimated basal energy needs to these patients during the transplant period. We have recently completed a pilot study in a cohort of pediatric allogeneic SCT patients in which parenteral energy intake was titrated to energy expenditure as measured by indirect calorimetry. We noted a substantial decline in resting energy expenditure (REE) during the course of SCT. When engraftment occurred, REE increased to near baseline levels. Since lean body mass is closely correlated with REE, and since SCT patients likely suffer lean body mass depletion with preparative chemotherapy regimens, we hypothesize that changes in body composition affect REE during the post-transplant period, and that standard nutritional support methods may lead to overfeeding. The primary outcome variable is body composition (as measured by dual energy x-ray absorptiometry, DXA), and secondary outcomes include glycemic control, frequency of infectious complications, and select biochemical parameters. Body composition measurements and energy expenditure studies have not been widely studied in pediatric stem cell transplant patients. This study will provide unique and detailed nutritional data on a group of catabolic pediatric patients, and the results will guide their nutritional therapy and may improve clinical outcomes. Children undergoing stem cell transplantation often require parenteral nutrition to provide adequate calories and protein due to severe mucositis and other gastrointestinal complications of the preparative regimen (1). Accurate provision of energy may reduce complications related to overfeeding (2) or underfeeding (3). We hypothesize that changes in body composition during SCT affect REE, and that the standard approach to nutritional management of these patients may lead to overfeeding. Specifically, we hypothesize that: 1. Children receiving nutritional support titrated to measured energy expenditure will have more optimal body composition (comparable lean body mass, lower percent body fat) than those provided nutritional support in the standard fashion. 2. Children receiving nutritional support titrated to measured energy expenditure will have improved glycemic control and decreased insulin resistance than those provided nutritional support in the standard fashion. 3. Compared with published norms, children undergoing SCT have altered rates of resting energy expenditure (REE). 4. Anticipated changes in REE are correlated with changes in lean body mass during SCT. 5. Children receiving nutritional support titrated to measured energy expenditure will resume oral intake sooner than those provided nutritional support in the standard fashion. SPECIFIC AIMS To conduct a randomized, double-blinded controlled clinical trial among pediatric SCT patients comparing two methods of nutritional support: 1) standard of care (the provision of 130-150% of estimated basal energy needs via parenteral nutrition), and 2) an experimental protocol in which energy intake is titrated to match resting energy expenditure as measured by indirect calorimetry. Primary Aims: 1. To compare the effects of standard vs. titrated nutritional support in pediatric SCT patients on percent body fat, as measured by DXA. 2. To compare the effects of standard vs. titrated nutritional support in pediatric SCT patients on glycemic control and insulin resistance. 3. To measure serial changes in REE over the course of SCT with indirect calorimetry. 4. To correlate anticipated changes in REE with changes in body composition. Secondary Aim: 1. To measure resumption of oral dietary intake after SCT. Malnutrition and Cancer: Cancer patients have a high incidence of malnutrition (4, 5). Children have increased energy needs for growth and are thus at greater risk of malnutrition than adults. Children undergoing stem cell transplantation are among those with highest nutritional risk due to their underlying disease and the intensive medical therapy prior to and following transplant (1). Significant declines in lean body mass and energy intake have been found in children undergoing chemotherapy (6, 7). High dose chemotherapy and total body irradiation as conditioning for SCT often produce painful oral mucositis that can reduce nutritional intake for days to weeks. Parenteral nutrition (PN) is routinely utilized during SCT since it has been associated with faster engraftment and improved survival (8, 9). Studies supporting the efficacy of PN, however, were performed in a single center nearly 20 years ago. Moreover, complications of PN include infections, hepatotoxicity, suppression of oral intake, and metabolic abnormalities. Provision of appropriate nutritional requirements while minimizing potential risks has been difficult without a clearer understanding of energy and nutrient needs of children undergoing SCT. Resting Energy Expenditure (REE) in Cancer Patients The energy needs of rapidly dividing cancer cells may increase basal metabolic demands of the host from 20 to 90% over predicted needs. Since basal energy needs account for a substantial portion of total energy needs, any increment in basal energy requirements can result in energy imbalance. Knox et al. (10) studied 200 adult cancer patients using the technique of indirect calorimetry, a non-invasive bedside measure of REE, the clinical estimate of basal metabolic rate (11). One-third of their patients were hypometabolic (REE was <90% of predicted levels), one fourth were hypermetabolic (REE >110% predicted), and the remaining 40% had normal REE (between 90 and 110% predicted). Older subjects, those with longer duration of disease, and underweight patients tended to have higher REE measurements. A small study of 6 autologous and 5 allogeneic adult SCT patients used indirect calorimetry prior to and during transplant. Allogeneic SCT patients had on average an 8% reduction in REE while autologous patients had an 11% increase, compared to predicted levels. This study suggests that the nutritional requirements of adults undergoing autologous or allogeneic SCT vary due to differences in treatment (12). Larger studies are needed to determine changes in requirements within each transplant group. Fewer studies of energy metabolism have been performed in children with cancer. Stallings et al. measured REE in 9 patients with ALL and found that patients with a higher tumor burden (elevated WBC count, organomegaly) had an increased REE (13). A study of 26 patients with ALL or solid tumors in remission showed no evidence of an increased resting energy expenditure, when compared to age- and sex-matched healthy controls (14). Using a combination of indirect calorimetry and ambulatory heart rate monitoring to measure REE and total energy expenditure (TEE) in 34 long-term survivors of ALL, Warner et al. concluded that ALL patients have lower levels of TEE largely related to reduced physical activity (15).